Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient
| Autor: | Kobus, K., Hartl, D., Ott, C.E., Osswald, M., Huebner, A., Hagen, M. von der, Emmerich, D., Kuhnisch, J., Morreau, H., Hes, F.J., Mautner, V.F., Harder, A., Tinschert, S., Mundlos, S., Kolanczyk, M. |
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| Přispěvatelé: | Clinical sciences |
| Rok vydání: | 2014 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Neurofibromatosis 1 Adolescent Adrenal Cortex/metabolism Science Loss of Heterozygosity Neurofibromatosis 1/genetics Adrenal Hyperplasia Congenital/genetics Mice Adrenocorticotropic Hormone Adrenocorticotropic Hormone/metabolism Animals Humans Child Medicine(all) Homeodomain Proteins Neurofibromin 1 Adrenal Hyperplasia Congenital nervous system diseases Child Preschool Adrenal Cortex Medicine Female Homeodomain Proteins/genetics Neurofibromin 1/genetics Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 10, Iss 3, p e0119030 (2015) PLoS One PLoS ONE, 10(3) |
| ISSN: | 1932-6203 |
| Popis: | BackgroundNeurofibromatosis type I (NF1, MIM#162200) is a relatively frequent genetic condition, which predisposes to tumor formation. Apart from tumors, individuals with NF1 often exhibit endocrine abnormalities such as precocious puberty (2,5-5% of NF1 patients) and some cases of hypertension (16% of NF1 patients). Several cases of adrenal cortex adenomas have been described in NF1 individuals supporting the notion that neurofibromin might play a role in adrenal cortex homeostasis. However, no experimental data were available to prove this hypothesis.Materials and methodsWe analysed Nf1Prx1 mice and one case of adrenal cortical hyperplasia in a NF1patient.ResultsIn Nf1Prx1 mice Nf1 is inactivated in the developing limbs, head mesenchyme as well as in the adrenal gland cortex, but not the adrenal medulla or brain. We show that adrenal gland size is increased in NF1Prx1 mice. Nf1Prx1 female mice showed corticosterone and aldosterone overproduction. Molecular analysis of Nf1 deficient adrenals revealed deregulation of multiple proteins, including steroidogenic acute regulatory protein (StAR), a vital mitochondrial factor promoting transfer of cholesterol into steroid making mitochondria. This was associated with a marked upregulation of MAPK pathway and a female specific increase of cAMP concentration in murine adrenal lysates. Complementarily, we characterized a patient with neurofibromatosis type I with macronodular adrenal hyperplasia with ACTH-independent cortisol overproduction. Comparison of normal control tissue- and adrenal hyperplasia- derived genomic DNA revealed loss of heterozygosity (LOH) of the wild type NF1 allele, showing that biallelic NF1 gene inactivation occurred in the hyperplastic adrenal gland.ConclusionsOur data suggest that biallelic loss of Nf1 induces autonomous adrenal hyper-activity. We conclude that Nf1 is involved in the regulation of adrenal cortex function in mice and humans. |
| Databáze: | OpenAIRE |
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